Alcohol use disorder (AUD), which is three times more common in schizophrenia (SCZ) than in the general population, worsens the course of this severe psychiatric disorder. Thus, the co-occurrence of AUD and SCZ is an important public health problem. While most available antipsychotic medications do not limit alcohol use in patients with SCZ, the atypical antipsychotic clozapine (CLOZ) appears to do so. However, because CLOZ has important side effects, its clinical use is limited to only the most severely ill patients with SCZ. Thus, new medications for the treatment of SCZ and AUD, medications at least as effective as CLOZ for limiting alcohol abuse in these patients, but safer than CLOZ, need to be found. We have developed a neurobiologic formulation of the action of CLOZ in patients with SCZ and AUD, and we have tested this formulation in groups of alcohol preferring rodents to begin to search for medications able to treat patients with SCZ and AUD. This neurobiologic formulation suggests that alcohol may enhance the functioning of a dysregulated dopamine- mediated mesocorticolimbic brain reward circuitry in patients with SCZ that underpins their use of alcohol. Further, this formulation also proposes that CLOZ, through its diverse effects on both dopaminergic and noradrenergic systems, is able to decrease alcohol use because it ameliorates the dysfunctional brain reward circuit in these patients. Recent studies by our group in alcohol-preferring hamsters and rats have suggested that the effect of CLOZ can be duplicated when medications possessing dopamine D2 receptor antagonism, norepinephrine a2 receptor antagonism and norepinephrine reuptake inhibition are combined together. These studies have indicated that the atypical antipsychotic risperidone (RISP), a medication producing antagonism at the dopamine D2 receptor and the norepinephrine a2 receptor, which by itself has a minimal ability to decrease alcohol drinking in patients with SCZ or in alcohol-preferring rodents, will decrease alcohol drinking in rodents when combined with the norepinephrine reuptake inhibitor desipramine (DMI). This proposed translational proof of concept R21 clinical trial seeks to extend the results of these animal studies into patients with SCZ and AUD. Our goal in this resubmitted application is to begin to assess whether RISP in combination with DMI will limit alcohol use in these patients. Our Specific Aims are: (1) To determine whether subjects who are treated with RISP in combination with DMI have less alcohol use (fewer drinking days; fewer heavy drinking days) than do patients who are treated with RISP alone; (2) To explore symptoms (of SCZ and of depression) in the two groups of patients: those treated with RISP in combination with DMI, as compared to those treated with RISP alone; and (3) To explore the medication side effect burden in the two groups of patients: those treated with RISP in combination with DMI, as compared to those treated with RISP alone. Information developed during this translational proof of concept trial will allow us to determine whether a larger clinical trial of RISP in combination with DMI should be undertaken in patients with SCZ and AUD. PUBLIC HEALTH RELEVANCE: Alcohol use disorder, which is common in patients with schizophrenia, worsens the course of this severe psychiatric disorder. This translational research proposal, based on studies in animals, seeks to begin to assess whether the combination of two commonly used medications, risperidone and desipramine, will limit alcohol use in patients with co-occurring schizophrenia and alcohol use disorder. Finding medications that may be able to limit alcohol use and thereby reduce adverse outcomes in patients with schizophrenia is of great public health importance.